Single amino acid variation (SAV) is one amino acid substitution resulting from genetic polymorphisms. The non-synonymous encoding variant would alter the protein sequence. However, in some extreme cases, this slight difference might affect the whole protein structure or function. Due to the unique physicochemical properties of each amino acid, the mutation in different positions of the sequence causes various effects for the whole protein conformation and its function. It is vital to understand how the single amino acid variation could influence protein and clarify the links between genetic variation and human disease. In previous studies, most disease-related SAVs occur in the structurally or functionally essential positions (Juritz et al., 2012; Sunyaev, Ramensky, & Bork, 2000; Yue, Li, & Moult, 2005). Just like some cases, as we have known, some conserved residues mutated, it could directly damage the native protein folding. These mutation residues might affect protein structure or the complex aggregation. Protein destabilization is a primary factor in many Mendelian diseases (Guo et al., 2011; Redler, Das, Diaz, & Dokholyan, 2016; Teng, Srivastava, Schwartz, Alexov, & Wang, 2010).